Osteoclasts (OC) are key mediators of erosive bone diseases, including tumor-associated osteolytic lesions, as well as rheumatoid arthritis (RA), other forms of arthritis, and osteoporosis. Indeed, OC are the only cells known to degrade bone. Osteoclastogenesis begins with differentiation of monocytes into OC precursor cells (OCP), which subsequently differentiate into multinucleated OC with bone resorption activity (Chiu, 2012). Studies with antibodies (Mensah, 2010) and knock-out/in models (Yagi, 2005) demonstrate an absolute requirement for the Dendritic Cell-Specific TrAnsMembrane Protein (DC-STAMP) for the fusion of OCP to generate fully active OC. Anti-DC-STAMP monoclonal antibodies attenuate the fusogenic process, reducing the number of active OC (Mensah, 2010) thus providing a unique approach to erosive bone diseases. Our Phase 1 goal is to identify and characterize a human monoclonal anti-DC-STAMP antibody (humAb) as a therapy for erosive bone diseases. We will construct a panel of humanized versions of DC-STAMP-specific mouse mAb 1A2, then express, purify, and characterize the candidate humAbs to be rank-ordered using an in vitro assays of binding, and osteoclastogenesis. The functional activity of the top anti-DC-STAMP humAb will then be evaluated in a mouse model to explore application for multiple myeloma-associated bone erosion. Successful identification of a DC-STAMP humAb will merit submission of a Phase 2 application to fund IND- enabling studies.